5-Lipoxygenase is the first dedicated enzyme in the pathway leading to the biosynthesis of leukotrienes (Samuelsson, B., "Leukotrienes: Mediators of Immediate Hypersensitivity Reactions and Inflammation," Science, 120: 568, 1983; Hammarstrom, S. Leukotrienes, Annual Review of Biochemistry, 52: 355, 1983). This important enzyme has a rather restricted distribution, being found predominantly in leukocytes and mast cells of most mammals. Normally 5-lipoxygenase is present in the cell in an inactive form; however, when leukocytes respond to external stimuli, intracellular 5-lipoxygenase can be rapidly activated. This enzyme catalyzes the addition of molecular oxygen to fatty acids with cis,cis-1,4-pentadiene structures, converting them to 1-hydroperoxy-trans,cis-2,4-pentadienes. Arachidonic acid, the 5-lipoxygenase substrate which leads to leukotriene products, is found in very low concentrations in mammalian cells and must first be hydrolyzed from membrane phospholipids through the actions of phospholipases in response to extracellular stimuli. The initial product of 5-lipoxygenase action on arachidonate is 5-HPETE which can be reduced to 5-HETE or converted to LTA.sub.4. This reactive leukotriene intermediate is enzymatically hydrated to LTB.sub.4 or conjugated to the tripeptide glutathione to produce LTC.sub.4. LTA.sub.4 can also be hydrolyzed nonenzymatically to form two isomers of LTB.sub.4. Successive proteolytic cleavage steps convert LTC.sub.4 to LTD.sub.4 and LTE.sub.4. Other products resulting from further oxygenation steps have also been described.
Products of the 5-lipoxygenase cascade are extremely potent substances which produce a wide variety of biological effects, often in the nanomolar to picomolar concentration range. (Sirois, P., Pharmacology of the Leukotrienes, Advances in Lipid Research, R. Paoletti, D. Kritchevesky, editors, Academic Press, 21: 79, 1985).
Leuokotrienes have been reported to be important mediators in several disease states including: Asthma, Allergic Rhinitis, Rheumatoid Arthritis, Gout, Psoriasis, Adult Respiratory Distress Syndrome, Inflammatory Bowel Disease, Endotoxin Shock, Ischemia-induced Myocardial Injury, Central Nervous Pathophysiology, and Atherosclerosis.
The enzyme 5-lipoxygenase catalyzes the first step leading to the biosynthesis of all the leukotrienes and therefore inhibition of this enzyme provides an approach to limit the effects of all the products of this pathway. Agents capable of abrogating the effects of these potent mediators of pathophysiological processes represent a promising class of therapeutic agents (Brooks, D. W., Bell, R. L., and Carter, G. W. Chapter 8. Pulmonary and Antiallergy Agents, Annual Reports in Medicinal Chemistry, Allen, R. C. ed., Academic Press 1988.)
U.S. Pat. No. 5,095,031 to Brooks, et. al. discloses and claims certain indole derivatives having utility for inhibiting lipoxygenase enzymes.
European Patent Application 87 311031.6 (Publication No. 0 275 667) to Gillard, et. al discloses and claims certain 3-(hetero-substituted)-N-benzylindoles as leukotriene biosynthesis inhibitors. See also 2nd International Conference on Leukotrienes and Prostanoids in Health and Disease, Oct. 9-14, 1988, Jerusalem, Israel, Abstract S5 and recently published, J. Gillard et. al., Can. J. Physiol. Pharmacol. 1989, 67, 456-464.